Di-substituted &#39; -phenethylcarbamic acid esters in the treatment of parkinsonism

ABSTRACT

Novel di-substituted .beta.-phenethylcarbamic acid esters. The compounds are useful as antidepressants and anti-Parkinsonism agents.

United States Patent [1 1 Biel'et al. Apr. 8, 1975 Dl-SUBSTITUTED [58] Field of Search 424/300 B-PHENETHYLCARBAMIC ACID ESTERS IN THE TREATMENT OF PARKINSONISM 5 References Cited [75] Inventors: John l-lans Biel, Lake Bluff, llL; UNITED STATES PATENTS Khmdt Brwkfield 3.600.427 8/3971 Verbiscar 260/471 c [73] Assignee: Aldrich Chemical Company,

Mflwallkee. Primary Examiner Stanley J. Friedman [22] Filed; 2 1973 Attorney, Agent, or FirmRobert L. Niblack; Joyce R.

Krei [2|] Appl. No.: 385,007

Related US. Application Data [57] ABSTRACT [62] Difisim of 1970' Novel di-substituted B-phenethylcarbamic acid esters.

The compounds are useful as antidepressants and anti- [52] US. Cl. 424/300; 424/244; 424/285; Parkinsonism agents 424/301 [5 I] Int. Cl A6lk 27/00 1 Claim, No Drawings Isl-SUBSTITUTED ,B-PHENETHYLCARBAMIC ACID ESTERS IN THE TREATMENT OF PARKINSONISM This is a division of application Ser. No. 96,586 filed Dec. 9, 1970.

BACKGROUND OF THE INVENTION Until recently, patients suffering from Parkinsonism were treated with anticonvulsants, antispasmodics, central nervous system stimulants, and the like, in an attempt to produce temporary amelioration of their complaints. In severe cases, surgical procedures were employed with some success. L-Dopa was the first single agent found to be effective in reversing the akinesia and rigidity of Parkinsonism, particularly in severe cases. An increase in mental alertness and wakefulness, relief from depression, and an increase in intellect has also been observed in patients receiving L-Dopa.

While L-Dopa has produced some rather promising results in experimental therapy and is being used in a limited number of patients, it is not well tolerated by a number of patients. The most frequent side effects are nausea, vomiting, postural hypostension, cardiac dysrhythmia and choreiform movements. The abnormal, involuntary movements pose severe problems to the drugs continued use in approximately 50% of the patients. Furthermore, dopamine itself is not orally active and has a very short duration of action. Thus, the search for more effective, orally-active, long-acting anti-Parkinson agents continues. it is an object of the present invention to provide such agents.

SUMMARY This invention relates to novel (ii-substituted B-phenethylcarbamic acid esters represented by the structural formula:

R 0 CH -CH -Nl-lC-OR wherein: R and R are hydrogen, benzyl, substituted benzyl, or

9 or E AR3,

wherein A is O, NH, or S, and R is lower alkyl, lower alkenyl, or lower alkynyl; and R, is lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, cyclopropyl- .methyl, ,B-(Z-furyU-ethyl or azetidinyl; with the limita- LII Lower alkenyl refers to both straight and branched chain alkenyl groups containing from 2 to 5 carbon atoms, such as vinyl, allyl, methallyl, 1-pentenyl,l and the like.

Lower alkynyl refers to C -C alkyl groups as defined above from which two hydrogen atoms have been removed from each of two adjacent carbon atoms to produce acetylenic unsaturation; e.g., propargyl, 2- butynyl, l-pentynyl, and the like. Substituted benzyl refers to a mono-, di-, or tri-substituted benzyl moiety substituted in the ortho, meta and/or para positions by a chloro, fluoro, iodo, bromo, or trifluoromethyl atom. Halo includes chloro, fluoro, bromo, and iodo. The anti-Parkinson activity of the above compounds was established using the Harmonyl (deserpidine) Antagonism Test. In the Harmonyl test, mice are dosed orally 'with 50 mg/kg of deserpidine 24 hours prior to drug evaluation. In mice, deserpidine produces ptosis, hunched posture, sedation, catalepsy and rigidity. L- Dopa produces marked reversal of the above effects in mice. Antagonism of the deserpidine effects in mice are graded slight (1), moderate (2) or marked (3), based on the reversal of the Harmonyl effects. The compounds of the invention produce moderate to marked reversal in dosages of from 10 to 200 mg/kg of body weight.

The compounds are generally administered to mammalian Parkinsonism patients in dosages of from 10 to 200 mg/kg of body weight daily, preferably in divided doses. While the compounds exhibit both oral and parenteral activity, the preferred route of administration is the oral route. The oral LD s of the compounds of this invention in mice are approximately 600-1,0QO mg/kg.

The antidepressant activity of the compounds of this invention was first established in the modified dopa test as described by Everett, et al., Fed. Proc., 23 p. 198 (1964). The compounds are useful as antidepressant agents when administered to depressed patients in dosages of from 10 to 200 mg/kg of body weight daily, preferably in divided doses.

Representative compounds of the present invention include 3,4-Dibenzyloxy-B-phenethylcarbamic acid, furfuryl ester, 3,4-Dihydroxy-B-phenethylcarbamic acid, ethyl ester, 3,4-Dihydroxy-B-phenethylcarbamic acid, isopropyl ester,

3,4-DihydroxyB-phenethylcarbamic acid, n-butyl ester,

3,4-Dibenzyloxy-62 -phenethylcarbamic acid, ,B-trichloroethyl ester,

3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester,

3,4-Dihydroxy-B-phenethylcarbamic acid, trichloroethyl ester.

3,4-Dihydroxy-B-phenethylcarbamic acid, 3azetidinyl ester,

3,4-Dibenzyloxy-B-phenethylcarbmic acid, cyclopropylmethyl ester, 3,4-Dithioethoxycarbonyl-B-phenethylcarbamic acid,

ethyl ester 3,4-Dimethoxycarbonyl-l3-phenethylcarbamic methyl ester 3,4-Dipropargyloxycarbonyl-B-phenethylcarbamic acid, propargyl ester, 3,4-Diallyloxycarabonyl-B-phenethylcarbamic allyl ester acid,

acid,

The method of synthesis of the compounds of this invention is represented by the following reaction scheme.

RACO Q 2 0t mom V o 11' RAC0@ CH -CH -NH C0 R mco Generally speaking protocatechualdehyde, l, (Aldrich Chemical Co.) is reacted with RC1 (i.e. benzyl chloride, etc.) to prepare 2-(wherein R=C H CH 2 is converted to the corresponding ,B-nitrostyrene, 3, which is treated with lithium aluminum hydride and the resulting amine 4 reacted with an appropriate chloroformate to prepare 5 (R=loweralkyl, etc.) or the amine 4 can be converted to the isocyanate 8 and then reacted with an appropriate alacohol to prepare 5. Removal of the catechol protecting group produces 6 which can be converted to 7(A=O, NH or S) by treating 6 with either an appropriate chloroformate or an isocyanate.

The following examples further illustrate the present invention.

EXAMPLE I PREPARATION of 3,4-DIBENZYLOXY-,B-PHENETHYLCARBAMIC ACID, ISOPROPYL ESTER A. 3,4-Dibenzyloxy-B-phenethylisocyanate In a 500 ml three necked flask equipped with a gas inlet tube and a Claisen head for distillation were placed 18.5 g (0.05 mole) of benzyloxydopamine hydrochloride in 350 ml of toluene. This was heated to reflux and 150 ml of toluene distilled off. The Claisen head was replaced with a reflux condenser equipped with a drying tube and phosgene was bubbled through the refluxing solution for four hours. The reaction was allowed to stand at room temperature overnight, filtered, and solvent removed in vacuo and the residue purified by a Kugelrohr distillation to give 14 g (78%) of 3,4-dibenzyloxy-B-phenethylisocyanate as a light yellow oil, b.p. 180 (0.05 mm).

RC1 cn uo no crro R0 Q no R tr-cii-No no R0 R0 Analysis Calcd. for C H NO C, 76.86; H, 5.89; N,

Found: C, 77.17; H, 5.75; N, 3.90 B. 3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester In a 50 ml flask equipped with a magnetic stirrer and a reflux condenser protected by a drying tube were placed 4.5 g (12.5 mole) of 3,4-dibenzyloxy-B- phenethylisocyanate, 20 ml of benzene, 1.3 ml of dry isopropanol and a crystal of bicycle [2,2,2] 1,4- diazaoctane. The reaction was heated at reflux for 20 hours. Removal of the solvent left a residue which contained the unreacted isocyanate. The residue was redissolved in 25 ml of benzene, 1.3 ml of isopropanol added and 2 drops of DBU (Aldrich-1,3-diazabicyclo[5,4,0]undec-5 ene) added. This was heated to reflux for 24 hours. The reaction was cooled, diluted with 25 ml of benzene, filtered and the solvent was removed in vacuo. The residue was dissolved in 150 ml of hot cyclohexane and set aside to crystallize. The white solid was filtered off and dried in vacuo to yield 2.1 g of 3,4- dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester, m.p. 80-83C.

Analys Calcd. for C H NO C, 74.44; H, 6.97; N,

3.34 Found: C, 74.68; H, 6.89; N, 3.41

EXAMPLES 2 9 l R10 CH2-CH2-NHC-OR4 fi l-i i Ex. Empirical M M n R1 R2 11,, 14.9. Formula 0 a n c a N 2 H H (CH3)2CH 91.5-92.5 CIZHHNOA 60.25 7.11 5.86 60.13 7.25 5.77 3 H n CCl CH 155 157 0 11 01 170 40.21 3.68 4.12 40.48 3.84 4.14 4 n a A411 118 119 C13H17N04 62.07 6.81 5.57 62.20 6.51 5.59 5 u a 9 D- 102 104 c n no 63.42 7.7 5.23 63.40 7.99 5.71 6 n c u c- 6 11 127 129 c a uo 56.64 6.40 4.71 56.71 6.44 4.60 7 'C6H5CH2 c u cn cn cc1 127.5-128.5 c n cmo, 59.01 4.75 2.75 59.16 4.63 2.88 -8 c u cn C6H5CH2 C l(Cl-l so 83 c a uo 74.44 6.97 3.34 74.68 6.89 3.41 9 c n cn C6H5CH2 ca t; 71 73 6 11 110 73.36 6.11 3.06 73.36 5.97 3.1

EXAMPLE commonly used in the art, such as water. Besides inert 3,4-DIHYDROXY-B-PHENETHYLCARBAMIC ACID, ETHYL ESTER A solution of 45 g of 3,4-dibenzyloxy-B-phenethylcarbamic acid, ethyl ester, prepared according to the method of Example 1, in 200 ml of ethanol containing 3 g of moist 10% Pd/C was hydrogenated at 40 psi. The reaction was filtered, evaporated to dryness and recrystallized from benzene to yield 18.4 g of product, m.p. 99l0l.

Analysis Calcd. for C, H, NO,: C, 58.65; H, 6.71; N,

FoundzC, 58.63; H, 6.58, N, 5.98

The compounds useful in the practice of the present invention are generally formulated into pharmaceutical compositions comprising, as an active ingredient, at least one of the active agents in association with a pharmaceutical carrier or diluent. The compounds useful in the practice of the invention exhibit both oral and parenteral activity and can be formulated in dosage forms for oral or parenteral administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets diluents, such compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected dosage depends upon the desired thereapeutic effect, on the route of administration, and on the duration of the treatment.

We claim:

1. A method of treating Parkinsonism by administering a therapeutically effective amount of a compound of the formula pensions, syrups, and elixirs containing inert diluents wherein R and R are the same or different members of the group consisting of hydrogen or benzyl, and R is loweralkyl, lowerhaloalkyl, cyclopropylmethyl or cyclopentyl to a patient in need of such treatment. 

1. A METHOD OF TREATING PARKINSONISM BY ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA 